PROJECT SUMMARY The goal of this fellowship is for the applicant (C. Paula de los Angeles) to learn advanced neuroimaging and network analysis methods and gain clinical exposure to the chronic neurological, developmental pediatric, and infectious disease care of youth with perinatally-acquired HIV with the long-term goal of becoming an independent physician-scientist. The applicant will receive further training in advanced neuroimaging and network analysis techniques in order to quantify overall and regional grey matter network characteristics. HIV affects over 36.9 million individuals worldwide, including three million children. Within the past two decades, the advent of combination anti-retroviral therapy (cART) has allowed youth with perinatally-acquired human immunodeficiency virus (PHIV) to survive into adulthood. HIV infection during a critical period of brain development may be particularly harmful to developing brains, with lasting effects in adulthood. In particular, youth with PHIV often demonstrate long-term cognitive deficits and developmental delay; globally, PHIV is a leading infectious cause of perinatally-acquired developmental disability. Despite cART, the brain remains a reservoir for latent HIV due to blood-brain barrier penetration and pharmacokinetic challenges. Neuroimaging studies in adults with horizontally- transmitted HIV have identified global and focal atrophy in brain regions with high HIV RNA. In particular, cortical thickness, an important measure of brain structural integrity used in studies of neurodevelopmental populations, is reduced globally and regionally in adults with HIV. Our understanding of the pathophysiology of cognitive deficits, including structural brain abnormalities, in youth with PHIV remains limited though clinically important. The purpose of this study is to use structural magnetic resonance imaging (sMRI) data and network analyses to characterize grey matter cortical thickness and structural covariance networks in youth with PHIV treated with cART and how this relates to HIV disease severity and cognitive performance. HIV disease severity is measured by historic peak HIV viral load and nadir CD4%. Cognitive performance is evaluated through extensive standardized neuropsychological assessment. I propose to achieve these goals through two specific aims. In Aim 1, I will compare grey matter structural integrity measures involved in neurodevelopment in youth with PHIV and uninfected youth. Structural integrity can be quantified in sMRI as regional cortical thickness, regional subcortical shape, and inter-regional structural covariance networks (SCNs), among others. SCNs, constructed by applying graph theory to sMRI data, have been used to quantify grey matter developmental coordination between brain regions and may reveal dysregulation in the setting of abnormal brain development. In Aim 2, I will determine relationships between structural integrity, HIV severity and cognition in youth with PHIV. I propose an innovative combination of advanced neuroimaging and graph theory to learn more about previously uncharacterized grey matter networks in youth with PHIV. We hope to inform clinical practice in youth with PHIV through an improved understanding of the long-term neuroanatomical and cognitive effects of PHIV on the brain.